1. Field of the Invention
This invention relates to certain 6a,7,9,9,10,10a-hexahydro-1-hydroxy-9-hydroxymethyl-3-substituted6H-dibenz o[b,d]pyrans and derivatives thereof useful as CNS agents, especially as analgesics and tranquilizers, in mammals, including man; and to intermediates therefor.
2. Description of the Prior Art
The search for new and improved analgesic agents has, for the past several years, centered upon cannabinol-type compounds. Large numbers of derivatives of such compounds and modification of the basic dibenzo[b,d]pyran ring system common to such compounds have been described in the literature. Several review articles have appeared which contain extensive bibliographies to the synthesis, structure, and biological properties of the naturally-occurring dibenzo[b,d]pyrans as well as to derivatives and modifications therefor. Of particular interest are the following review articles: R. Mechoulam, Ed., "Marijuana. Chemistry, Pharmacology, Metabolism and Clinical Effects", Academic Press, New York, N.Y. 1973; Mechoulam, et al, Chemical Reviews, 76, 75-112 (1976). In addition to these review articles from the chemical literature, rather comprehensive reviews appear in U.S. Pat. Nos. 3,886,184 and 3,968,125. However, despite the large numbers of such compounds described in the literature, the search for new and improved agents continues thus pointing to the lack of an agent useful for the control of broad levels of pain and accompanied by a minimum of side-effects.
U.S. Pat. No. 3,968,125, issued July 6, 1976, describes a series of 6a,7,8,9,10,10a-hexahydro-1-hydroxy-3-alkyl-6H-dibenzo[b,d]pyran-9-ols useful as hypotensive agents, as psychotropic drugs, particularly as anti-anxiety and/or antidepressant drugs, and as sedative and/or analgesic drugs.
Mechoulam, Ed., "Marijuana. Chemistry, Pharmacology, Metabolism and Clinical Effects", Academic Press, New York, N.Y., 1973, at page 58, describes 6a,7,8,10a-tetrahydro-1-hydroxy-3-alkyl-6,6-dimethyl-9-hydroxymethyl-6H-di benzo[b,d]pyran and 6a,7,10,10a-tetrahydro-1-hydroxy-3-alkyl-6,6-dimethyl-9-hydroxymethyl-6H-d ibenzo[b,d]pyran, which are metabolites of the corresponding tetrahydrocannabinols having a methyl group at the 9-position.
Razdan et al., J. Am. Chem. Soc., 95, 2361-2 (1973) describe 7-hydroxyhexahydrocannabinol and a compound "tentatively unidentified" as its C.sub.1 -epimer.
In addition to the problem of addiction liability, the opiate analgesics have a limited use in the treatment of chronic pain states such as cancer because tolerance to the analgesic activity is developed upon repeated administration of these drugs. While the potent 9-hydroxy-dibenzo[b,d]pyran analgesics represent a therapeutic advance since they are non-narcotic drugs, it has been found that rapid tolerance develops to their analgesic action thereby limiting the use of these agents in chronic pain states where repeated dosing over long periods of time is necessary to provide continued pain relief.